Fertile Ground

The discoveries of many treatments for disorders of the brain resulted from happenstance. Iproniazid, the first modern antidepressant, was originally designed as a tuberculosis drug, while a second-generation antidepressant, imipramine, represented a failed attempt to treat schizophrenia. But levodopa, or L-dopa, was meant for exactly the purpose it serves: helping people with Parkinson’s disease overcome the tremors, rigidity and problems with balance that stem from the loss of specialized neurons that produce dopamine. Levodopa replenishes depleted dopamine, a brain chemical crucial for motor control, to dramatic effect.

During his residency in the 1970s, Warren Olanow, now a neuroscientist at the Mount Sinai School of Medicine in New York City, was amazed to see patients, nearly paralyzed by Parkinson’s, stand up and walk after taking the drug. But miraculous as it may be, L-dopa has a serious side effect: dyskinesia, jerky movements that can be as disturbing as the original problems of Parkinson‘s. What’s more, the longer a patient has lived with this progressively degenerative disease, the shorter the drug’s good effect lasts. Still, the temporary balm of L-dopa raises an intriguing possibility that has preoccupied Olanow and others. Could the brain itself be restored, not just by adding a missing chemical but by replacing lost cells and rebuilding decaying neural circuits?

For years the less favored alternative to L-dopa was surgery. To alleviate both the rigidity of Parkinson’s and the dyskinesia caused by L-dopa, the overly active globus pallidus, located deep within the brain in the basal ganglia, was lesioned in a procedure called a pallidotomy. To quell tremors, part of the thalamus, at the top of the brain stem, was destroyed in a thalamotomy. Other brain disorders were treated surgically as well: To subdue severe epilepsy, surgeons targeted the tissue in which seizures arise, usually in one of the temporal lobes. For major depression and other severe psychiatric diseases, the approach was to cut out tissue with a cingulotomy, usually in the anterior cingulate cortex, which was thought to be the emotional center of the brain. Some of these procedures are still used, though recently a few have been supplanted by deep brain stimulation, in which implanted electrodes inactivate specific brain regions.

Cutting away parts of the brain—or turning them off—carries the risks of major surgery and may come with such side effects as memory loss and depression. But until recently, there seemed little point in trying to save aberrant tissue, because scientists thought it was irreparable. As Santiago Ramón y Cajal, who won the Nobel Prize in medicine in 1906, said of neurons, “Everything may die; nothing may be regenerated.” The dogma held that people are born with a given number of neurons that, unlike most cells in the body, cannot divide or be replenished.

That outlook changed when Fred H. Gage of the Salk Institute for Biological Studies in La Jolla, Calif., demonstrated that neurons in certain brain regions can sometimes reproduce themselves, in a process called neurogenesis, raising the possibility that aberrant brain tissue isn’t beyond help after all. “Now, instead of removing or disabling parts of the brain, neuroscientists can think about restoring the malfunctioning organ, either by recruiting the body’s own regenerative capabilities or by adding therapeutic cells and molecules to discrete regions,” says Miles Cunningham, a neuropsychiatrist at McLean Hospital in Belmont, Mass.

The first clinical attempts to restore the brain using transplanted neurons actually started during the late 1980s, even before the revelations about neurogenesis, but the growing understanding of the brain’s innate powers is improving these efforts and expanding the arsenal of restorative neuroscience. So far most studies have focused on such neurodegenerative conditions as Parkinson’s, stroke, spinal cord injuries and epilepsy. But Cunningham is interested in using restorative methods to treat depression and other psychiatric disorders.

2. “Stem Cell Transplantation for Neurodegenerative Diseases,” by Anne E. Rosser, Rike Zietlow and Stephen B. Dunnett, Current Opinion Neurology, December 2007. The authors present early evidence that adult neural stem cells and other immature neurons can be transplanted into selected brain regions to restore functions lost as a result of neurodegenerative diseases.